Cancer Flashcards
Mechanism of action of methotrexate
- inhibits dihydrofolate reductase (DHFR) → blocks conversion of dihydrofolate to tetrahydrofolate.
- A depletion of tetrahydrofolate leads to thymidylate deficiency which is vital for DNA synthesis. 3. This inhibits DNA synthesis, particularly in rapidly dividing cells and leads to cell death.
What phase is methotrexate and 5FU(capecitabine) specific to
S-phase
What is the dose limiting toxicity of methotrexate
Bone marrow suppression
What group of chemotherapy agents cause oral mucositis
Mainly antimetabolites
What drugs are high risk for alopecia
- Methotrexate
- Anti Microtubules agents(taxanes and vincaalkaloids)
- Anthracyclines(doxorubicin)
What is the kidney supportive care for methotrexate
Pre and post treatment hydration: IV fluids including 100mEq HCO3- until urine pH is 7 and maintain this pH throughout therapy
What is Leucovorin and when is it given
Folinic acid.
Give 24 hours after MTX chemotherapy, to reduce side effects and save bone marrow cells . Also used and rescue therapy in MTX overdose
What is the emesis risk of methotrexate
Minimal = Oral MTX
Low < 250mg/m2
Moderate > 250 mg/m2
What is the extravasation risk of methotrexate
Irritant
What do you monitor with methotrexate
FBC
MTX concentration at 24 hours.
Bilirubin and LFT(hepatoxic)
* temporary rise between dosese but not true liver impairment
Renal function tests baseline and every cycle
What are the 5 mechanisms of resistance to MTX
- Efflux pumps
- Reduce expression of folate carrier protein (impaired uptake)
- Overexpression of target protein (Dihydrofolate reductase)
- Mutation in target protein-
- Reduced retention (increased polyglutamylation or increased break down of polyglutamates)
Can 5-FU be taken orally
No because it has reduced absorption.
Prodrug capecitabine is used instead.
What is mechanism of action of 5-FU
Inhibits thymidylate synthase + additional mechanism
1. 5FU converted to metabolite FdUMP
2. FdUMP binds thymidylate synthase
3. Fluorine ion prevents reaction from occurring thus forms stable complex with thymidylate synthase and co-factor tetrahydrofolate.
4. No synthesis of DNA precursors: purine and pyrimidines
5. apoptosis
additional mechanism: to incorporate into DNA and RNA disrupting normal functioning and processes(poorly understood)
What is the dose limiting toxicity of capecitabine
Diarrhoea (leads to dehydration and renal failure)
Bone marrow suppression(if given by IV bolus)
What is the emesis risk of 5FU and capecitabine
LOW
How do you treat diarrhoea associated with Capecitabine
- Loperamide
- Oral Rehydration Sachets,
- Codeine(add/replace lop)
- if severe octreotide(somatostain analogue which reduces GI motility)
What deficiency should be tested for on capecitabine
Dihydropyrimidine dehydrogenase deficiency before initiating treatment
DPD metabolises capecitabine, if there is deficiency higher risk of toxicities, contraindicated.
What is are toxicities of capecitabine
- Diarrhoea
- mucositis
- BMS
- Peripheral neuropathy
What 3 drugs causes peripheral neuropathy
- Vincristine
- Capacitabine
- Paclitaxel
How do you manage peripheral neuropathy caused by chemotherapy
Pyridoxine 50mg PO TDS
Transcutaneous Electrical Nerve Stimulation(TENS)
Acupunture
Severe - gabapentin or pregabalin
What are the symptoms of peripheral neuropathy
Change in sensation
Increased sensitivity
Pain
Numbness
Muscle weakness
Coordination or balance issues
Loss of finger movement
What are the 3 mechanisms of resistance to 5FU/capacitabine
- Increase target protein expression
- mutation in target protein
- Increased catabolism by dihydropyrimidine dehydrogenase(DPD)
What is the difference between capecitabine and 5FU
capecitabine is oral prodrug of 5FU, it is converted to 5FU in 3 stages by enzymes which are higher in cancerous cells which makes it more specific.
What drug class is cyclophosphamide
Alkylating agent
Is cyclophosphamide and prodrug
Yes
Are alkylating agents and alkylating like agents cycle specific
No
DNA can be accessed at any point
What is the dose limiting toxicity of cyclophosphamide
Bone marrow suppression
What are other toxicities of cyclophosphamide
Hemorrhagic cystitis
What is hemorrhagic cystitis
Hemorrhagic cystitis irritation of the bladder lining caused by breakdown product called acrolein
What is the emesis risk of Cyclophosphamide
> 1500mg/m2 High emesis risk >90% incidence
<1500mg/m2 Moderate emesis risk (30-90%)
What is the extravasation risk of cyclophosphamide
Non-vesicant (nuetral)
When do you give aprepitant
Anthracycline+ cyclophosphamide
High dose cisplatin (70mg/m2)
What is hemastix
Testing for blood in urine
What is mesna
Mesna binds to acrolein and removes it.
When is mesna given prophylactically
Mesna is always given to patients receiving cyclophosphamide doses of 1g/m2 or more (can be oral or iv), and all doses of ifosfamide
What is the mechanism of action of cyclophosphamide
It binds to the N7 position of guanine and forms cross links either intrastrand or interstrand. Interstrand crosslinks prevent the DNA from being unwound thus stopping DNA transcription and replication from occuring –> apoptosis
What treatment may be used to treat neutropenia
immediate admission for broad-spectrum antibiotic therapy (piperacillin-tazobactam & gentamicin)
Granulocyte-colony stimulating factor(GCSF) i.e filgrastim Stimulates the production of neutrophils.
What are the 3 resistance mechanisms for cyclophosphamide
- Impaired uptake
- DNA repair mechanisms which can remove the cross-linking - nucleotide excision repair(NER) which removes bulky adducts.
- Body produces glutathione which is an antioxidant that neutralises alkylating ag
What class is mephalan
Alkylating agent
What is the mechanism of action of melphalan
It binds to the N7 position of guanine and forms cross links either intrastrand or interstrand. Interstrand crosslinks prevent the DNA from being unwound thus stopping DNA transcription and replication from occuring –> apoptosis
Dose limiting toxicity of melphalan
Bone marrow suppression
What is the emesis risk of melphalan
Moderate risk if dose above 100mg/m2
Minimal risk if oral therapy
what are the 4 resistance mechanisms for melphalan
- Overexpression of efflux pumps
- Impaired uptake
- DNA excision repair mechanisms
- Body produces glutathione which is an antioxidant that neutralises alkylating agents.
What drug class is doxorubicin
Anthracyclines
What enzyme does doxorubicin inhibit
Topoisomerase II
What is the role of Topoisomerase II
Maintaining the integrity of DNA and regulating the coiling of DNA
Doxorubicin 3 MOA’s
- Stabilises Topo2 and DNA complex (transient breaks cannot be resealed)
- Intercalates into DNA bases, disrupting the helical structure
- Produces reactive oxygen species, that cause DNA damage
is doxorubicin cell cycle specific
Non -cycle specific
What is the dose limiting toxicity for doxorubicin
Cardiotoxicity
-oxygen free radicals usually detoxified by catalase but heart has low catalase activity
What is doxorubicin cardiotoxicity cumulative lifetime dose
around 450 -550mg/m2
What is a non toxic side effect of doxorubicin
colours urine red
What is the emesis risk of doxorubicin
LOW risk for liposomal doxorubicin
MODERATE = < 60mg/m2
HIGH = > 60mg/m2 OR given with cyclophosphamide
What is extravastion risk with doxorubicin
DNA binding vesicant
Doxorubicin is a bright red solution
What are the two types of vesicants and the difference between them
DNA binding or non-DNA binding.
bind to DNA –> cell death, drug then released –> further more extensive damage
doesnt bind to DNA –> get metabolised in tissue–> local damage
How do you treat extravasation of DNA BINDING vesicants (LN)
- stop the infusion but leave cannula in place
- aspirate the area
- Mark the extravasated area with a pen
- remove cannula
- COLD(constricts vessels stops spread) compress 20mins QDS for 1-2 days
- Neutralise - Use specific antidotes(Anthracyclines- dexrazoxane)
- elevate limb+ analgesia
How to mitigate cardiotoxicity of doxorobicin
- Slow infusion rather than bolus prevents high peak plasma concentrations and high exposure to free radicals
- using liposomal formulations
- dexrazoxane - iron chelator prevents cardiotoxicity by bind to free radicals
- use of ACE inhibitors, ARBs and beta blockers
How do you treat extravasation of NON-DNA BINDING vesicants (DD)
- stop the infusion but leave cannula in place
- aspirate the area
- Mark the extravasated area with a pen
- remove cannula
6.warm (speed up distribution for metabolism) compress 20mins QDS for 1-2 days - dilute - hyaluronidase (vinca alkaloids and taxanes)
- elevate limb+ analgesia
How do you treat extravasation of irritant
- stop the infusion but leave cannula in place
- aspirate the area
- Mark the extravasated area with a pen
- remove cannula
- Saline flush out
How do you treat extravasation of non-vesicant
- Local dry cold compress
- elevate and pain relief
What should you monitor for doxorubicin
FBC, LFT, U&Es
ECG every 3 months of treatment
MUGA scan( LVEF ),
Baseline MUGA is the are predisposed to heart failure, have hypertension or are a smoker.
What is MUGA scan
heart functioning, radioactive tracer injected into blood stream and a GAMMA camera is used to see how blood is being pumped through the heart and left ventricular ejection fraction (LVEF) is measure.
3 mechanisms of resistance to Doxorubicin
Efflux pump overexpression
Anti-oxidant such as gluthaione
Mutation in target protein
What type of drug is Etoposide
Non-anthracycline Topoisomerase II inhibitors
Etoposide MOA
stabilize topoisomerase II DNA complex, preventing DNA from re-sealing and leading to double strand breaks
- The accumulation of DNA double strand breaks leads to apoptosis
What part of the cycle is etoposide specific to
S and G2 phases
What is the extravasation risk with etoposide
irritant
Mechanisms of resistance to etoposide
- Efflux pump –(PGP and MDR1)
- Mutations in Topoisomerase II
- Increased DNA repairing mechanisms.
What happens is etoposide is infused too quickly
Low blood pressure
What are the two dose limiting toxicities of etoposide
Mucositis at high doses
Myelosuppression
What 2 drugs are microtubules inhibitors
Vincristine
Paclitaxel
Vincristine MOA
Inhibits microtubule polymerization by binding to beta-tubulin, thus preventing the assembly of microtubules
-This disrupts formation of mitotic spindle = leads to metaphase arrest and eventual apoptosis of rapidly dividing cells
What cell cycle phase is vincristine and paclitaxel specific to
M-phase
What is the extravasation risk of Vincristine
Non-DNA binding vesicant
emesis risk of vincristine
minimal risk(Less than 10%)
How does vincristine affect LFTs
transient rise post treatment
What supportive care with vincristine
- Cold cap
- GCSF
- Peripheral
- Neuropathy (pyridoxine)
What are the 3 resistance mechanism for vincristine
- Overexpression of efflux pumps PGP
- Mutations in target proteins
- Overexpression of target protein
Dose limiting toxicity of vincristine
Peripheral Neuropathy
+
Nuetropenia
What class of drug is bleomycin
Cytotoxic antibiotic
Bleomycin 2 mechanism of action
- Bleomycin forms a complex with Fe2+(pseudoenzyme). This complex under goes redox reactions to form superoxide and hydroxide free radicals that cleave DNA.
- Inhibit DNA polymerase a key enzyme required for DNA synthesis.
What phase is bleomycin specific to
G2 phase
What is the dose limiting toxicity of bleomycin
Pulmonary toxicity (pulmonary fibrosis)
What is monitoring for bleomycin
Chest X-ray
Lung function tests
Respiratory symptoms
renal function - reduce dose
4 resistance mechanism for bleomycin
- Increased antioxidant production by the cancerous cell i.e. glutathione S-transferase
- Increased DNA repair mechanisms
- Impaired uptake
- Increased efflux
Bleomycin extravasation risk?
Non- vesicant
Bleomycin emesis risk
minimal
Paclitaxel MOA
Binds to beta-tubulin and stabilizes it (stabilizes microtubules), which prevents microtubule disassembly, and essentially locks them in place = disrupts cell division and induces apoptosis
Dose limiting toxicity of paclitaxel
Neutropenia
paclitaxel emesis risk
low/moderate(idk not in list)
Paclitaxel extravasation risk
Non-DNA binding vesicant
Paclitaxel is high risk of what non-toxic side effect
Alopecia
what component in paclitaxel causes hypersensitivity reactions
Cremophor EL
What premedication is given with paclitaxel to prevent hypersensitivity reactions
Dexamethasone and histamine antagonist (chloramphenamine)
What are the 3 mechanisms for resistance for paclitaxel
- Mutations in target protein tubulin which prevents binding.
- Overexpression of tubulin
- Pgp efflux
What is the mechanism of action of cisplatin
Enters cells via passive diffusion and CTR1
- aquation where Cl- ligands replaced with water (aqua-ligand displacement) and becomes positively charged. binding to to N7 guanine of DNA, where it forms intra-strand and inter-strand cross links (DNA is negatively charged and can bind to positively charged ligand complex) = preventing DNA replication and transcription (predominantly intra-strand)
What is the dose limiting toxicity of cisplatin
Nephrotoxicity
What are 3 toxicity of cisplatin(excluding nephrotoxicity)
- Ototoxicity(hearing loss)
- Peripheral neuropathy
- Bone marrow suppression
What is the emesis risk for cisplatin
more than 70mg/m2 high emesis risk(90%+incidence)
less than 70mg/m2 moderate emesis risk (30-90% incidence)
Cisplatin extravasation
Irritant
What is the supportive care for cisplatin
Pre and post IV fluids for hydration + Furosemide
Anti-emetics
What monitoring is there for cisplatin
- CrCL + U & E
- LFT + Billirubin
- Hearing tests(Ototoxicity)
- FBC
5.Signs of peripheral nueropathy
4 resistance mechanisms for cisplatin
- Over expression of efflux pumps
- Impaired uptake
- NER – dna repair mechanism
- Anti-oxidant
What is tamoxifen
A selective oestrogen receptor modulator
When is oestrogen used
For ER+ breast cancers(Pre/post menopausal women)
Either pre or post debulking to prevent recurrence
Tamoxifen MOA
Oestrogen stimulates proliferative signalling that enables cells to enter the mitosis especially in breast tissue. In ER+ breast cancers oestrogen causes uncontrolled proliferative signalling leading to tumour growth. Tamoxifen is structurally similar to estrogen, such that it can bind to the oestrogen receptor. However, it produces antagonistic effects, as it prevents endogenous estrogen from binding as a result, preventing proliferative signalling such that cells remain static cannot progress into the cell cycle.
What phase does tamoxifen act
G0/ G1 phase
What is DLT of tamoxifen
Does not have DLT
What toxicities of tamoxifen
Hot flushes, irregular menses and discharge.
Thromboembolism(VTE and PE)
Increased risk of endometrial cancer(agonistic effects)
Emesis risk of tamoxifen
Low(less than 10% incidence)
Extravasation risk of tamoxifen
No risk as Oral
Supportive therapy for tamoxifen
Regular breast screening
Stockings on flights
Hot flush/sweats - l/s advice like menopause
Vaginal dryness - non-hormonal lubricants
Mood swings - SNRIs
Resistance mechanisms for tamoxifen
None
What is herceptin
Humanised monoclonal antibody trastuzumab
What are the 3 mechanisms of action for herceptin
Binds to extracellular domain of HER2 receptor(receptor for epidermal growth factor which overexpressed in breast cancer cells)
- By binding to this, it inhibits receptor signalling pathways (MAPK and P13 and AKT pathways), preventing cell proliferation
- HER2 degradation via ubiquitination - Modification of protein which degrades HER2 (small protein ubiquitin binds to target protein)
- ADCC (antibody dependent cell cytotoxicity) –monoclonal antibody attracts immune cells (natural killer cells)
What is the dose limiting toxicity of herceptin
Cardiotoxicity(Heart failure and LVEF)
LVEF must be above limit
Why does herceptin cause cardiotoxicity
Down regulates neuregulin which maintains cardiac functioning
What should monitor with herceptin
LVEF(baseline and before each cycle)
Signs of heart failure(SOB etc)
3 Resistance mechanism to herceptin
- Intra-cellular alterations in HER downstream signalling (upregulation) i.e loss of the PTEN pathway which suppress the proliferative pathways. Thus more active P13K/AKT proliferative pathways –>tumour growth
- truncated HER-2 receptors(removal of extracellular domain such that Herceptin cannot bind)
- Elevating other tyrosine kinase receptors to activate downstream proliferative signalling pathways.
What is gleevec
A tyrosine kinase inhibitior
Imatinib
How does gleevec work
It works by binding to the ATP binding site of tyrosine kinase, which is important for the phosphorylation of tyrosine residues which initiates downstream signalling.
What phase of the cell cycle does trastuzumab act G1 phase
Cellular arrest at the G1
What is supportive therapy for imatinib
Adequate hydration and allopurinol 300mg OD to prevent tumour lysis syndrome
3 resistance mechanisms to imatinib
Mutations in kinase domain of Bcr-ABl = drug cannot bind to it.
Overexpression of Bcr-Abl (BCR-ABL:drug ratio is altered, meaning that BCR-ABL can still stimulate signalling)
Increased efflux.
